Various phosphorylated forms of phosphatidylinositol are critical regulators of many cell functions, including primary metabolism, growth and proliferation of cells, differentiation, cell migration, immune responses, and apoptosis. Because they are involved in many aspects of cell regulation, it is not always predictable what effect a drug candidate may have when it inhibits conversion of phosphatidylinositol between its various phosphorylated forms. For example, FIG. 1 illustrates some of the known roles played by phosphatidylinositol-4,5-diphosphate (PI-4,5-P2, also referred to herein as PIP2) and phosphatidylinositol-3,4,5-triphosphate (PI-3,4,5-P3, also referred to herein as PIP3). PIP3 activates a number of receptors, some of which are involved in cell growth, replication, and death (apoptosis).
It has recently been reported that the tumor suppressor Pten is mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. Pten's major substrate is PIP3, which it dephosphorylates to form PIP2. Its strong association with liver cancers in particular suggests that Pten is especially important for maintaining homeostasis and preventing tumor formation in the liver. It has also been shown that hepatocyte-specific Pten deficiency leads to steatohepatitis and hepatic carcinomas. Y. Horie, et al., J. Clin. Investigation, 113(12), 1774-83 (2004). Horie concludes that controlled blocking of the PI3K pathway may be beneficial for treatment of patients predisposed to NASH, liver cirrhosis or hepatic carcinomas. It has also been reported recently that steatosis (accumulation of fat) induced by exposure of hepatocytes to conditions that generate reactive oxygen species can be inhibited by LY294002, an inhibitor of kinases that phosphorylate PIP2 to form PIPS. R. Kohli, et al., J. Biol. Chem. 282, 21327-36 (July 2007). Kohli demonstrated that LY294002 blocked steatosis development in a model system where diet induced p85 expression and steatosis, demonstrating that an inhibitor of PI3Ks can prevent development of steatosis.
Liver disorders are increasingly common due to high calorie diets and high obesity rates in the developed world. These are risk factors for fatty liver conditions that can progress to cirrhosis. NASH (non-alcoholic steatohepatitis) is one such condition: it was first identified in 1980, but is now a widely recognized condition affecting millions of Americans. Kohli, et al. As many as 30 million Americans are believed to have nonalcoholic fatty liver disease (FALD), and about 30% of those are believed to have NASH. Methods to treat liver disorders associated with excessive fatty deposits are therefore needed. The present invention provides compounds and methods for preventing and/or treating such conditions.